The present application relates to production of chiral intermediates for total synthesis of (-)- and (+)-opioids by the method disclosed in U.S. patent application Ser. No. 165,690 filed July 3, 1980. Since all medically important opium derivatives, including thebaine, can be manufactured from intermediates prepared in the above-mentioned disclosure, the simple and effective methods described below for synthesis of chiral precursors are of fundamental importance. In addition to affording intermediates for production of (-)-opioids (natural), the present disclosure also permits synthesis of intermediates useful for preparing (+)-opioids which are of importance as antitussive agents and neuropharmacological research tools.
The synthesis outlined for the total short synthesis of dihydrothebainone, dihydrocodeinone, and nordihydrododeinone is shown schematically in the following outline. ##STR1##
As a general summary of the above chart, the following general description is made commencing with codeine (1).
Racemic dihydrothebainone (19), nordihydrocodeinone (21) and dihydrocodeinone (22) were synthesized in high overall yield from 3-methoxyphenethylamine (4), via the key intermediate (.+-.)-1-bromonordihydrothebainone (18); the route utilized unprotected phenolic intermediates, involved directed Grewe-type cyclization and for 21 and 22, exploited novel oxide bridge closure in the N-nor series.
Heating a mixture of amine (4) and pure acid (5) afforded amide (6). Cyclization of 6 generated an aqueous solution of the 1,2-dihydro derivative of 7, not shown on the chart. This derivative is the starting point for the novel asymmetric synthesis of this invention. (The possibility for resolution of racemic tetrahydroisoquinoline 7 is suggested in the parent application.) Birch reduction with lithium and ammonia afforded 8. Refluxing 8 with PhOCHO or chloral gave 10. A solution of 10 and ethylene glycol generated a solution of ketal 11 and subsequently bromoketal 12 was produced. Grewe-type cyclization produced 17. Refluxing 17 in MeOH-aqueous HCl yielded 18. 19 is available from 17 by hydrogenation in the presence of formaldehyde. Synthesis routes from 18 yield 19, 21, and 22. Specific details are found in the parent application, incorporated by reference.
Conversion of (-)-19 to (-)-thebaine (3) and (-)-codeine (1) and facile O-demethylation of the latter to (-)-morphine (2) provide a practical total synthesis of these natural alkaloids.